Hepatic targeting of the centrally active cannabinoid 1 receptor (CB1R) blocker rimonabant via PLGA nanoparticles for treating fatty liver disease and diabetes

Cannabinoformins: Designing Biguanide-Embedded, Orally Available, Peripherally Selective Cannabinoid-1 Receptor Antagonists for Metabolic Syndrome Disorders

“…22,30 An additional approach for peripheral CB 1 R antagonism using nano-formulation was recently shown to be effective in rodent models. 47 The 3,4-dihyrdopyrazoline scaffold is a privileged scaffold and in order to exploit the therapeutic potential of CB 1 R antagonism on this scaffold, we have developed a novel paradigm, which engages a dual-target or multi-target platform to enhance the efficacy via disparate and related synergistic mechanisms to alleviate multifactorial pathologies. Detailing this new approach, we now show that the methyl group in ibipinabant can be replaced to achieve peripheral restriction and exploit concomitant beneficial therapeutic effects that could result from this replacement (Figure 2).…”

“…Incorporation of glycine or l -valine amide side attachment in lieu of methanamine on the central pyrazoline core led to JD5006 and JD5037, with further reduction in brain penetrance (Figure ). JD5037 was further characterized as a non-brain-permeable CB 1 R inverse agonist devoid of adverse behavioral effects but retaining the metabolic benefits of ibipinabant. , These molecules and similar compounds are undergoing de-risking studies. , An additional approach for peripheral CB 1 R antagonism using nano-formulation was recently shown to be effective in rodent models . The 3,4-dihyrdopyrazoline scaffold is a privileged scaffold and in order to exploit the therapeutic potential of CB 1 R antagonism on this scaffold, we have developed a novel paradigm, which engages a dual-target or multi-target platform to enhance the efficacy via disparate and related synergistic mechanisms to alleviate multifactorial pathologies.…”